Adenovirus-mediated gene transfer of the beta(2)-adrenergic receptor to donor hearts enhances cardiac function

Gene transfer to modify donor heart function during transplantation has sig nificant therapeutic implications. Recent studies by our laboratory in tran sgenic mice have shown that overexpression of beta(2)-adrenergic receptors (beta(2)-ARs) leads to significantly enhanced cardiac function. Thus, we in vestigated the functional consequences of adenovirus-mediated gene transfer of the human beta(2)-AR in a rat heterotopic heart transplant model. Donor hearts received 1 ml of solution containing 1 x 10(10) p.f.u. of adenoviru s encoding the beta(2)-AR or an empty adenovirus as a control. Five days af ter transplantation, basal left ventricular (LV) pressure was measured usin g an isolated, isovolumic heart perfusion apparatus. A subset of hearts was stimulated with the beta(2)-AR agonist, zinterol. Treatment with beta(2)-A R virus resulted in global myocardial gene transfer with a six-fold increas e in mean beta-AR density which corresponded to a significant increase in b asal contractility (LV + dP/dt(max), control: 3152.1 +/- 286 versus beta(2) -AR, 6250.6(star) +/- 432.5 mmHg/s; n = 10, P-star < 0.02). beta(2)-AR over expressing hearts also had higher contractility after zinterol administrati on compared with control hearts. Our results indicate that myocardial funct ion of the transplanted heart can be enhanced by the adenovirus-mediated de livery of beta(2)-ARs. Thus, genetic manipulation may offer a novel therape utic strategy to improve donor heart function in the post-operative setting .